Our hypothesis is that human epileptic hippocampal neurons undergo morphological changes, including aberrant axonal projections, and that reorganization of local synaptic circuitry through these structural changes has the potential to greatly alter membrane excitability and synaptic transmission and perhaps give rise to chronic seizures. This hypothesis is based on our findings of 1) identification of the trajectories of aberrant axon collaterals in human epileptic dentate granule cells (DGCs) and 2) intracellular recording from these neurons indicating an increased excitatory synaptic transmission mediated by the NMDA receptor. Studies in kainate-treated animals in vivo and in vitro support our hypothesis demonstrating substantial changes in both synaptic excitation and inhibition in "reorganized" DGC circuits. The objectives of the proposed studies are 1) to determine the nature of neurophysiological changes that are dependent on the reorganized local neuron circuit and 2) to determine to what extent these physiological changes are involved in modulating the excitation-inhibition balance of epileptic hippocampus. Hippocampal slice preparations offer an excellent experimental system to investigate these fundamental and important aspects of human temporal lobe epilepsy. Using intracellular and extracellular recordings, whole-cell patch clamp recording, and exogenous application of receptor agonists and antagonists, we propose to study: 1) Excitability of DGCs in relation to the presence of regenerated aberrant mossy fiber collaterals. Involvement of ionotropic and metabotropic glutamate receptors in aberrant neurotransmission will be investigated electrophysiologically and pharmacologically. The degree of excitation will be correlated to aberrant collateral reorganization; 2) GABA-ergic inhibition and its neuron circuit will be examined by isolating IPSPs pharmacologically and by directly stimulating and recording from inhibitory neurons in a laminar specific manner. Strength of recurrent inhibition via an hypothesized aberrant circuit will be examined by recording inhibitory responses from DGCs. 3) In parallel with human experiments, we will conduct animal studies using the kainate model. This will provide control comparisons to our human experiments and assist our analyses and interpretations of experimental outcomes in human studies. In addition, we will examine the effect of mossy fiber axotomy on DGC excitability. The effect of possible zinc increase on the excitability of regenerated DGCs will be separated from aberrant circuit properties using zinc chelators. The objective is to understand the effect of morphological alterations on neuronal discharges in epileptic, seizure-susceptible hippocampus in humans.